Cancer is a collection of complex genetic diseases characterized by multiple defects in the homeostatic mechanisms that regulate cell growth, proliferation and differentiation. Although the analysis of human tumor specimens has allowed the identification of many molecules and pathways important for the malignant phenotype, we still lack a complete understanding of the events that conspire to program any specific type of cancer. Recent advances in developing human experimental models of cancer have provided new insights into the pathways whose perturbation is necessary to achieve cell transformation. These studies indicate that many combinations of genetic mutations confer tumorigenicity on human cells and that both cell-type and tumor-stromal interactions play critical roles in dictating the tumor phenotype.